DESCRIPTION: (adapted from application): For over 25 years, this grant has funded the development of novel tools of general utility which the P.I. and others have used to solve specific genetic problems. During the current grant period, the funded research progressed from developing gene targeting for modifying specific genes in mice, to studying single gene diseases, and now to study common diseases with a complex multigenic mode of inheritance. In this new research, three areas have been identified where improvements are required. The investigator indicates a need: to extend the range of functional changes that can be made in genes; to be able to disable homeostatic feedback loops that often mask the effects of single gene mutations in complex systems; to be able to predict the most informative combinations of individual gene mutations, since testing all possible combinations is logistically impractical and unacceptably wasteful of living animals. Four specific aims, each contributing to the overall project goal of developing a deep understanding of the genetic bases of common multifactorial diseases, are: (1) To develop additional molecular tools for varying the function of chosen genes; (2) To develop means of disabling homeostasis in complex genetic systems; (3) To develop computer models able to replicate already known effects of changes in individual genes within complex genetic systems; and (4) To predict from computer simulations and then examine experimentally in mice combinations of single gene mutations that are particularly deleterious and/or will test the genetic and molecular relationships which underlie the computer models.